Exposure to methylphenidate (a dopamine reuptake inhibitor) mimics several behavioral and molecular effects of cocaine. However, other cocaine-like effects are minimal, possibly because serotonin is not elevated by methylphenidate. This notion is supported by recent findings produced in the applicants' laboratories, showing that elevating serotonin with selective serotonin reuptake inhibitors (SSRIs) potentiates methylphenidate-induced psychomotor activity and neuronal adaptations in brain regions implicated in psychostimulant addiction. It is currently unknown if increasing the serotonin transmission with SSRIs in conjunction with methylphenidate could also promote addiction. This is of concern because many individuals are being exposed to a drug combination of methylphenidate (Ritalin) plus an SSRI. The objective of this application is to determine how methylphenidate+SSRI exposure modifies indicators of cocaine addiction liability. The hypothesis is that SSRIs potentiate the effects of methylphenidate, making it more cocaine-like. Repeated exposure to methylphenidate+SSRI will thus facilitate the subsequent development of cocaine self-administration behavior, which is an indicator of cocaine addiction liability. This will be tested in rats, using paradigms that allow inferring sensitivity and motivation to self-administer cocaine (Aim 1a) and compulsive drug taking (Aim 1b). Exposure to methylphenidate+SSRI could also trigger relapse in ex-cocaine users. This will be tested in rats, using paradigms that measure reinstatement of drug seeking behavior (Aim 2). Successful completion of these aims is significant, as it will inform a decision of whether or not methylphenidate+SSRI drug combinations should be avoided in the future because of their potential to facilitate behavioral changes related to psychostimulant addiction. PUBLIC HEALTH RELEVANCE: Serotonergic agents such as selective serotonin reuptake inhibitors (SSRIs, Prozac) and dopaminergic agents such as methylphenidate (Ritalin) are widely used in mental health disorders such as attention-deficit hyperactivity disorder and depression. In addition, methylphenidate is frequently used as a cognitive enhancer. In these studies, we will establish if a combination treatment of methylphenidate (Ritalin) plus an SSRI (Prozac) produces cocaine-like behavioral changes indicative of increased addiction liability, and thus should be avoided.